The tumor microenvironment as a key regulator of radiotherapy response.

Radiotherapy (RT) remains a cornerstone of cancer treatment, yet its efficacy is often limited by tumor recurrence and resistance. Emerging evidence underscores the pivotal role of the tumor microenvironment (TME) in this process. RT-induced vascular damage exacerbates hypoxia, a key driver of resistance, while activation of cancer-associated fibroblasts promotes fibrosis and extracellular matrix remodeling that shield tumor cells. Furthermore, RT elicits a complex immune response, capable of both immunogenic cell death and fostering an immunosuppressive milieu enriched with regulatory T cells and myeloid-derived suppressor cells. We discuss the mechanisms through which these TME alterations, hypoxia, fibrotic signaling, and immune evasion, collectively contribute to RT resistance and recurrence. In this review, we summarize current knowledge on how RT remodels the TME, focusing on its dualistic impact on vascular integrity, stromal activation, and immune regulation. Finally, we outline the promising therapeutic strategies in overcoming TME-mediated resistance, including vascular normalization, targeting hypoxia-inducible factors, and combining RT with immunotherapies such as immune checkpoint blockade. Overall, a deeper understanding of TME dynamics post-RT is crucial for developing novel combination therapies to improve clinical outcomes.